Muscarinic Receptors and Alzheimer’s Disease

Abstract

Alzheimer ś disease (AD) is the most common neurodegenerative disorder in humans and it is characterized by the presence of two aberrant structures in the brains of affected patients: senile plaques and neurofibrillary tangles (NFTs). Senile plaques (SPs) are primarily composed of aggregated oligomers of the amyloid-b peptide, a fragment of the amyloid precursor protein (APP) that is produced by its sequential cleavage by two proteases, band g-secretase [1]. In addition, α-secretase also cleaves APP within the amyloid-b sequence, preventing the formation of amyloid-b and its assembly. The main component of NFTs is the phosphorylated form of the microtubule-associated protein, tau [2]. Over 30 years ago, AD was linked with a severe loss of cholinergic markers in the brains of patients [3,4], which led to the proposal that the loss of cholinergic neurons was related to the severity of dementia [5] and the cholinergic deficit hypothesis of AD [6]. Later, genetic studies suggested a fundamental role for the amyloid peptide in the onset of AD, giving rise to the amyloid hypothesis [7]. In this article, I will describe a possible relationship between the amyloid peptide, tau protein and cholinergic (mainly muscarinic) receptors in AD. Although the b-amyloid peptide is known to promote neurotoxicity by binding to α 7 nicotinic receptors [8], we will mainly focus here on muscarinic receptors. Five cholinergic muscarinic receptor subtypes (muscarinic acetylcholine receptors) are expressed in the CNS [9], M1 to M5, all members of the G protein coupled receptor family. M1, M3 and M5 couple to the Gq/G 11 family and activate phospholipase C upon agonist binding. By contrast, M2 and M4 receptors couple to Gi/G 0 proteins and they are associated with effector systems that inhibit adenylate cyclase activity [10,11]. M1 and M3 are the most abundant mAChRs in the hippocampus and enthorinal cortex of the adult mouse, while M5 is poorly expressed in these brain areas [9]. Autoradiographic analysis of the M1–M4 receptor subtypes revealed a significant decrease in all of these receptors in the enthorinal cortex and in most hippocamal